"The focus of the CMBS is pediatric neuroectodermal tumors including neuroblastoma, brain tumors and Ewings sarcoma. Retinoic Acid(RA) induced differentiation of neuroblastoma tumor cell lines continues to be our model for studies that define the signal transduction paths that mediate growth control, differentiation and cell death. Using a series of receptor selective retinoids ligands we found that RAR and RXR nuclear receptors are required to mediate maximal growth inhibiting and differentiating effects of retinoids. The most active combinations were ligands that activated RARbeta;RXR heterodimers followed by ligands activiating RARalpha:RXR and RARgamma:RXR. We identified one agonist that was more potent than RA & 9cisRA in inhibiting growth and inducing differentiation, whether this compound has clinical utility remains to be evaluated. Differential display was utilized to identify genes that may be selectively activated by these agonists. Several candidate differentially displayed mRNA have been isolated, cloned and are under investigation. We have determined that the molecular mechanisms by which retionids causes a G1 arrest of cell growth in NB cells is via a complete inhibition of G1 cyclin-dependent kinases. The decrease in kinase activity is caused by an increase in p27kip and its binding to G1 cyclin-dependent kinases. As the increase in p27 is not transcriptionally regulated, it may be due to the RA induced decrease in N-myc which leads to a desequestration of p27. The expression of G1 cyclins and cdks and other inhibitors are unchanged during RA treatment. In NB tumors, Trks serve as tumor markers; TrkA is expressed in good prognosis tumors and most poor prognosis tumor express TrkB. We have found that the differential activation of these signal transduction pathways in NB may alter their growth, invasiveness, chemosensitivity and cell survival. Using tet-regulated expression vectors we have made a series of NB cells which express varying levels of Trk and are testing the effects of activation of these paths on cell growth. We find that NGF treatment of cells expressing high levels of TrkA causes a marked decrease in cell number by delaying but not arresting progression through the cell cycle. This is associated with decreases in N-myc and increases in p27 binding to cdk-kinases. Thus using RA or NGF we find decreases in N-myc and increases in p27 associated with growth inhibition."